RESUMO
Enhancers provide critical information directing cell-type-specific transcriptional programs, regulated by binding of signal-dependent transcription factors and their associated cofactors. Here, we report that the most strongly activated estrogen (E2)-responsive enhancers are characterized by trans-recruitment and in situ assembly of a large 1-2 MDa complex of diverse DNA-binding transcription factors by ERα at ERE-containing enhancers. We refer to enhancers recruiting these factors as mega transcription factor-bound in trans (MegaTrans) enhancers. The MegaTrans complex is a signature of the most potent functional enhancers and is required for activation of enhancer RNA transcription and recruitment of coactivators, including p300 and Med1. The MegaTrans complex functions, in part, by recruiting specific enzymatic machinery, exemplified by DNA-dependent protein kinase. Thus, MegaTrans-containing enhancers represent a cohort of functional enhancers that mediate a broad and important transcriptional program and provide a molecular explanation for transcription factor clustering and hotspots noted in the genome.
Assuntos
Elementos Facilitadores Genéticos , Receptor alfa de Estrogênio/metabolismo , Fatores de Transcrição/metabolismo , Estrogênios/metabolismo , Fator de Transcrição GATA3/metabolismo , Regulação da Expressão Gênica , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Complexos Multiproteicos/metabolismoRESUMO
Distal enhancers characterized by the H3K4me(1) mark play critical roles in developmental and transcriptional programs. However, potential roles of specific distal regulatory elements in regulating RNA polymerase II (Pol II) promoter-proximal pause release remain poorly investigated. Here, we report that a unique cohort of jumonji C-domain-containing protein 6 (JMJD6) and bromodomain-containing protein 4 (Brd4) cobound distal enhancers, termed anti-pause enhancers (A-PEs), regulate promoter-proximal pause release of a large subset of transcription units via long-range interactions. Brd4-dependent JMJD6 recruitment on A-PEs mediates erasure of H4R3me(2(s)), which is directly read by 7SK snRNA, and decapping/demethylation of 7SK snRNA, ensuring the dismissal of the 7SK snRNA/HEXIM inhibitory complex. The interactions of both JMJD6 and Brd4 with the P-TEFb complex permit its activation and pause release of regulated coding genes. The functions of JMJD6/ Brd4-associated dual histone and RNA demethylase activity on anti-pause enhancers have intriguing implications for these proteins in development, homeostasis, and disease.
Assuntos
Elementos Facilitadores Genéticos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Proteínas Nucleares/metabolismo , RNA Polimerase II/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Gênica , Proteínas de Ciclo Celular , Células HEK293 , Humanos , Regiões Promotoras Genéticas , RNA Nuclear Pequeno/metabolismoRESUMO
The functional engagement between an enhancer and its target promoter ensures precise gene transcription1. Understanding the basis of promoter choice by enhancers has important implications for health and disease. Here we report that functional loss of a preferred promoter can release its partner enhancer to loop to and activate an alternative promoter (or alternative promoters) in the neighbourhood. We refer to this target-switching process as 'enhancer release and retargeting'. Genetic deletion, motif perturbation or mutation, and dCas9-mediated CTCF tethering reveal that promoter choice by an enhancer can be determined by the binding of CTCF at promoters, in a cohesin-dependent manner-consistent with a model of 'enhancer scanning' inside the contact domain. Promoter-associated CTCF shows a lower affinity than that at chromatin domain boundaries and often lacks a preferred motif orientation or a partnering CTCF at the cognate enhancer, suggesting properties distinct from boundary CTCF. Analyses of cancer mutations, data from the GTEx project and risk loci from genome-wide association studies, together with a focused CRISPR interference screen, reveal that enhancer release and retargeting represents an overlooked mechanism that underlies the activation of disease-susceptibility genes, as exemplified by a risk locus for Parkinson's disease (NUCKS1-RAB7L1) and three loci associated with cancer (CLPTM1L-TERT, ZCCHC7-PAX5 and PVT1-MYC).
Assuntos
Fator de Ligação a CCCTC/genética , Elementos Facilitadores Genéticos , Predisposição Genética para Doença , Regiões Promotoras Genéticas , Sistemas CRISPR-Cas , Proteínas de Ciclo Celular/genética , Células Cultivadas , Cromatina , Proteínas Cromossômicas não Histona/genética , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Células MCF-7 , Neoplasias/genética , Células-Tronco Neurais , Oncogenes , Doença de Parkinson/genética , CoesinasRESUMO
Cell dormancy is a widespread mechanism used by bacteria to evade environmental threats, including antibiotics. Here we monitored bacterial antibiotic tolerance and regrowth at the single-cell level and found that each individual survival cell shows different "dormancy depth," which in return regulates the lag time for cell resuscitation after removal of antibiotic. We further established that protein aggresome-a collection of endogenous protein aggregates-is an important indicator of bacterial dormancy depth, whose formation is promoted by decreased cellular ATP level. For cells to leave the dormant state and resuscitate, clearance of protein aggresome and recovery of proteostasis are required. We revealed that the ability to recruit functional DnaK-ClpB machineries, which facilitate protein disaggregation in an ATP-dependent manner, determines the lag time for bacterial regrowth. Better understanding of the key factors regulating bacterial regrowth after surviving antibiotic attack could lead to new therapeutic strategies for combating bacterial antibiotic tolerance.
Assuntos
Trifosfato de Adenosina/metabolismo , Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Metabolismo Energético/efeitos dos fármacos , Proteínas de Escherichia coli/metabolismo , Escherichia coli/efeitos dos fármacos , Agregados Proteicos , Endopeptidase Clp/genética , Endopeptidase Clp/metabolismo , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Concentração de Íons de Hidrogênio , Viabilidade Microbiana/efeitos dos fármacos , Análise de Célula Única , Fatores de TempoRESUMO
Nuclear receptors induce both transcriptional activation and repression programs responsible for development, homeostasis, and disease. Here, we report a previously overlooked enhancer decommissioning strategy underlying a large estrogen receptor alpha (ERα)-dependent transcriptional repression program. The unexpected signature for this E2-induced program resides in indirect recruitment of ERα to a large cohort of pioneer factor basally active FOXA1-bound enhancers that lack cognate ERα DNA-binding elements. Surprisingly, these basally active estrogen-repressed (BAER) enhancers are decommissioned by ERα-dependent recruitment of the histone demethylase KDM2A, functioning independently of its demethylase activity. Rather, KDM2A tethers the E3 ubiquitin-protein ligase NEDD4 to ubiquitylate/dismiss Pol II to abrogate eRNA transcription, with consequent target gene downregulation. Thus, our data reveal that Pol II ubiquitylation/dismissal may serve as a potentially broad strategy utilized by indirectly bound nuclear receptors to abrogate large programs of pioneer factor-mediated, eRNA-producing enhancers.
Assuntos
Elementos Facilitadores Genéticos , Receptor alfa de Estrogênio/genética , Proteínas F-Box/genética , Fator 3-alfa Nuclear de Hepatócito/genética , Histona Desmetilases com o Domínio Jumonji/genética , Ubiquitina-Proteína Ligases Nedd4/genética , RNA Polimerase II/genética , Sequência de Bases , Sítios de Ligação , Sistemas CRISPR-Cas , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Proteínas F-Box/metabolismo , Edição de Genes/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Células MCF-7 , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Ligação Proteica , RNA/genética , RNA/metabolismo , RNA Polimerase II/metabolismo , Transdução de Sinais , Transcrição Gênica/efeitos dos fármacos , Ubiquitinação/efeitos dos fármacosRESUMO
The molecular mechanisms underlying the opposing functions of glucocorticoid receptors (GRs) and estrogen receptor α (ERα) in breast cancer development remain poorly understood. Here we report that, in breast cancer cells, liganded GR represses a large ERα-activated transcriptional program by binding, in trans, to ERα-occupied enhancers. This abolishes effective activation of these enhancers and their cognate target genes, and it leads to the inhibition of ERα-dependent binding of components of the MegaTrans complex. Consistent with the effects of SUMOylation on other classes of nuclear receptors, dexamethasone (Dex)-induced trans-repression of the estrogen E2 program appears to depend on GR SUMOylation, which leads to stable trans-recruitment of the GR-N-CoR/SMRT-HDAC3 corepressor complex on these enhancers. Together, these results uncover a mechanism by which competitive recruitment of DNA-binding nuclear receptors/transcription factors in trans to hot spot enhancers serves as an effective biological strategy for trans-repression, with clear implications for breast cancer and other diseases.
Assuntos
Neoplasias da Mama/metabolismo , Receptor alfa de Estrogênio/metabolismo , Regulação Neoplásica da Expressão Gênica , Receptor Cross-Talk , Receptores de Glucocorticoides/metabolismo , Transcrição Gênica , Sítios de Ligação , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Dexametasona/farmacologia , Regulação para Baixo , Elementos Facilitadores Genéticos , Estradiol/farmacologia , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Células MCF-7 , Complexos Multiproteicos , Mutação , Correpressor 1 de Receptor Nuclear/genética , Correpressor 1 de Receptor Nuclear/metabolismo , Correpressor 2 de Receptor Nuclear/genética , Correpressor 2 de Receptor Nuclear/metabolismo , Ligação Proteica , Interferência de RNA , Receptor Cross-Talk/efeitos dos fármacos , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/genética , Transdução de Sinais , Sumoilação , Transcrição Gênica/efeitos dos fármacos , Transcriptoma , TransfecçãoRESUMO
BACKGROUND: An accelerated epidemiological transition, spurred by economic development and urbanization, has led to a rapid transformation of the disease spectrum. However, this transition has resulted in a divergent change in the burden of infectious diseases between urban and rural areas. The objective of our study was to evaluate the long-term urban-rural disparities in infectious diseases among children, adolescents, and youths in China, while also examining the specific diseases driving these disparities. METHODS AND FINDINGS: This observational study examined data on 43 notifiable infectious diseases from 8,442,956 cases from individuals aged 4 to 24 years, with 4,487,043 cases in urban areas and 3,955,913 in rural areas. The data from 2013 to 2021 were obtained from China's Notifiable Infectious Disease Surveillance System. The 43 infectious diseases were categorized into 7 categories: vaccine-preventable, bacterial, gastrointestinal and enterovirus, sexually transmitted and bloodborne, vectorborne, zoonotic, and quarantinable diseases. The calculation of infectious disease incidence was stratified by urban and rural areas. We used the index of incidence rate ratio (IRR), calculated by dividing the urban incidence rate by the rural incidence rate for each disease category, to assess the urban-rural disparity. During the nine-year study period, most notifiable infectious diseases in both urban and rural areas exhibited either a decreased or stable pattern. However, a significant and progressively widening urban-rural disparity in notifiable infectious diseases was observed. Children, adolescents, and youths in urban areas experienced a higher average yearly incidence compared to their rural counterparts, with rates of 439 per 100,000 compared to 211 per 100,000, respectively (IRR: 2.078, 95% CI [2.075, 2.081]; p < 0.001). From 2013 to 2021, this disparity was primarily driven by higher incidences of pertussis (IRR: 1.782, 95% CI [1.705, 1.862]; p < 0.001) and seasonal influenza (IRR: 3.213, 95% CI [3.205, 3.220]; p < 0.001) among vaccine-preventable diseases, tuberculosis (IRR: 1.011, 95% CI [1.006, 1.015]; p < 0.001), and scarlet fever (IRR: 2.942, 95% CI [2.918, 2.966]; p < 0.001) among bacterial diseases, infectious diarrhea (IRR: 1.932, 95% CI [1.924, 1.939]; p < 0.001), and hand, foot, and mouth disease (IRR: 2.501, 95% CI [2.491, 2.510]; p < 0.001) among gastrointestinal and enterovirus diseases, dengue (IRR: 11.952, 95% CI [11.313, 12.628]; p < 0.001) among vectorborne diseases, and 4 sexually transmitted and bloodborne diseases (syphilis: IRR 1.743, 95% CI [1.731, 1.755], p < 0.001; gonorrhea: IRR 2.658, 95% CI [2.635, 2.682], p < 0.001; HIV/AIDS: IRR 2.269, 95% CI [2.239, 2.299], p < 0.001; hepatitis C: IRR 1.540, 95% CI [1.506, 1.575], p < 0.001), but was partially offset by lower incidences of most zoonotic and quarantinable diseases in urban areas (for example, brucellosis among zoonotic: IRR 0.516, 95% CI [0.498, 0.534], p < 0.001; hemorrhagic fever among quarantinable: IRR 0.930, 95% CI [0.881, 0.981], p = 0.008). Additionally, the overall urban-rural disparity was particularly pronounced in the middle (IRR: 1.704, 95% CI [1.699, 1.708]; p < 0.001) and northeastern regions (IRR: 1.713, 95% CI [1.700, 1.726]; p < 0.001) of China. A primary limitation of our study is that the incidence was calculated based on annual average population data without accounting for population mobility. CONCLUSIONS: A significant urban-rural disparity in notifiable infectious diseases among children, adolescents, and youths was evident from our study. The burden in urban areas exceeded that in rural areas by more than 2-fold, and this gap appears to be widening, particularly influenced by tuberculosis, scarlet fever, infectious diarrhea, and typhus. These findings underscore the urgent need for interventions to mitigate infectious diseases and address the growing urban-rural disparity.
Assuntos
Doenças Transmissíveis , Escarlatina , Tuberculose , Criança , Adolescente , Humanos , Doenças Transmissíveis/epidemiologia , China/epidemiologia , DiarreiaRESUMO
BACKGROUND: This study aimed to investigate the differences in the microbiota composition of serum exosomes from patients with acute and chronic cholecystitis. METHOD: Exosomes were isolated from the serum of cholecystitis patients through centrifugation and identified and characterized using transmission electron microscopy and nano-flow cytometry. Microbiota analysis was performed using 16S rRNA sequencing. RESULTS: Compared to patients with chronic cholecystitis, those with acute cholecystitis exhibited lower richness and diversity. Beta diversity analysis revealed significant differences in the microbiota composition between patients with acute and chronic cholecystitis. The relative abundance of Proteobacteria was significantly higher in exosomes from patients with acute cholecystitis, whereas Actinobacteria, Bacteroidetes, and Firmicutes were significantly more abundant in exosomes from patients with chronic cholecystitis. Furthermore, functional predictions of microbial communities using Tax4Fun analysis revealed significant differences in metabolic pathways such as amino acid metabolism, carbohydrate metabolism, and membrane transport between the two patient groups. CONCLUSIONS: This study confirmed the differences in the microbiota composition within serum exosomes of patients with acute and chronic cholecystitis. Serum exosomes could serve as diagnostic indicators for distinguishing acute and chronic cholecystitis.
Assuntos
Colecistite Aguda , Colecistite , Exossomos , Microbioma Gastrointestinal , Microbiota , Humanos , RNA Ribossômico 16S/genética , Microbioma Gastrointestinal/genética , Fezes/microbiologia , Microbiota/genéticaRESUMO
Certain long non-coding RNAs (lncRNAs) have potential peptide-coding abilities. Here, the role and molecular basis of the RNF217-AS1-encoded peptide in stomach cancer (SC) tumorigenesis were explored. Here, lncRNAs associated with SC pathogenesis and macrophage infiltration and lncRNAs with peptide-coding potential were searched by bioinformatics analysis. The gene mRNA and protein levels were examined by RT-qPCR and western blot assays, respectively. Cell viability, migratory, and invasive abilities were measured by CCK-8, Transwell migration, and Transwell invasion assays, respectively. The potential biological processes related to lncRNA RNF217-AS1 were identified by single-gene GSEA analysis. The effect of RNF217-AS1-encoded peptide on SC tumorigenesis was examined by mouse xenograft experiments. The results showed that lncRNA NR2F1-AS1 and RNF217-AS1 were differentially expressed and associated with macrophage infiltration in SC, and they had the ability to translate into short peptides. The RNF217-AS1 ORF-encoded peptide could reduce SC cell viability, inhibit cell migration and invasion, as well as hinder the development of SC xenograft tumors. The RNF217-AS1 ORF-encoded peptide in human SC AGS cells suppressed THP-1 cell migration, triggered the differential expression of CXCL1/CXCL2/CXCL8/CXCL12, and inactivated the TLR4/NF-κB/STAT1 signaling pathways. As a conclusion, the RNF217-AS1 ORF-encoded peptide hindered SC progression in vitro and in vivo and suppressed macrophage recruitment and pro-inflammatory responses in SC.
Assuntos
Carcinogênese , Movimento Celular , Macrófagos , RNA Longo não Codificante , Neoplasias Gástricas , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Humanos , Animais , Camundongos , Macrófagos/metabolismo , Carcinogênese/genética , Linhagem Celular Tumoral , Peptídeos/genética , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , Inflamação/metabolismo , Inflamação/genética , Proliferação de CélulasRESUMO
Enhancers for embryonic stem (ES) cell-expressed genes and lineage-determining factors are characterized by conventional marks of enhancer activation in ES cells1-3, but it remains unclear whether enhancers destined to regulate cell-type-restricted transcription units might also have distinct signatures in ES cells. Here we show that cell-type-restricted enhancers are 'premarked' and activated as transcription units by the binding of one or two ES cell transcription factors, although they do not exhibit traditional enhancer epigenetic marks in ES cells, thus uncovering the initial temporal origins of cell-type-restricted enhancers. This premarking is required for future cell-type-restricted enhancer activity in the differentiated cells, with the strength of the ES cell signature being functionally important for the subsequent robustness of cell-type-restricted enhancer activation. We have experimentally validated this model in macrophage-restricted enhancers and neural precursor cell (NPC)-restricted enhancers using ES cell-derived macrophages or NPCs, edited to contain specific ES cell transcription factor motif deletions. DNA hydroxyl-methylation of enhancers in ES cells, determined by ES cell transcription factors, may serve as a potential molecular memory for subsequent enhancer activation in mature macrophages. These findings suggest that the massive repertoire of cell-type-restricted enhancers are essentially hierarchically and obligatorily premarked by binding of a defining ES cell transcription factor in ES cells, dictating the robustness of enhancer activation in mature cells.
Assuntos
Diferenciação Celular/genética , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica/genética , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Células-Tronco Pluripotentes/metabolismo , Fatores de Transcrição/metabolismo , Animais , Epigênese Genética , Feminino , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Especificidade de Órgãos , Células-Tronco Pluripotentes/citologia , Reprodutibilidade dos TestesRESUMO
Natural variations in gene expression provide a mechanism for multiple phenotypes to arise in an isogenic bacterial population. In particular, a sub-group termed persisters show high tolerance to antibiotics. Previously, their formation has been attributed to cell dormancy. Here we demonstrate that bacterial persisters, under ß-lactam antibiotic treatment, show less cytoplasmic drug accumulation as a result of enhanced efflux activity. Consistently, a number of multi-drug efflux genes, particularly the central component TolC, show higher expression in persisters. Time-lapse imaging and mutagenesis studies further establish a positive correlation between tolC expression and bacterial persistence. The key role of efflux systems, among multiple biological pathways involved in persister formation, indicates that persisters implement a positive defense against antibiotics prior to a passive defense via dormancy. Finally, efflux inhibitors and antibiotics together effectively attenuate persister formation, suggesting a combination strategy to target drug tolerance.
Assuntos
Antibacterianos/farmacologia , Proteínas da Membrana Bacteriana Externa/metabolismo , Compostos de Boro/farmacologia , Farmacorresistência Bacteriana , Proteínas de Escherichia coli/metabolismo , Escherichia coli/efeitos dos fármacos , Proteínas de Membrana Transportadoras/metabolismo , Penicilinas/farmacologia , Antibacterianos/metabolismo , Proteínas da Membrana Bacteriana Externa/genética , Transporte Biológico , Compostos de Boro/metabolismo , Contagem de Colônia Microbiana , Relação Dose-Resposta a Droga , Farmacorresistência Bacteriana/genética , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Regulação Bacteriana da Expressão Gênica , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Membrana Transportadoras/genética , Viabilidade Microbiana/efeitos dos fármacos , Mutação , Imagem Óptica , Penicilinas/metabolismo , Fenótipo , Fatores de Tempo , Regulação para CimaRESUMO
KEY MESSAGE: The silencing of GhGASA14 and the identification of superior allelic variation in its coding region indicate that GhGASA14 may positively regulate flowering and the response to GA3. Gibberellic acid-stimulated Arabidopsis (GASA), a member of the gibberellin-regulated short amino acid family, has been extensively investigated in several plant species and found to be critical for plant growth and development. However, research on this topic in cotton has been limited. In this study, we identified 38 GhGASAs that were dispersed across 18 chromosomes in upland cotton, and all of these genes had a GASA core domain. Transcriptome expression patterns and qRT-PCR results revealed that GhGASA9 and GhGASA14 exhibited upregulated expression not only in the floral organs but also in the leaves of early-maturing cultivars. The two genes were functionally characterized by virus-induced gene silencing (VIGS), and the budding and flowering times after silencing the target genes were later than those of the control (TRV:00). Compared with that in the water-treated group (MOCK), the flowering period of the different fruiting branches in the GA3-treated group was more concentrated. Interestingly, allelic variation was detected in the coding sequence of GhGASA14 between early-maturing and late-maturing accessions, and the frequency of this favorable allele was greater in high-latitude cotton cultivars than in low-latitude ones. Additionally, a significant linear relationship was observed between the expression level of GhGASA14 and flowering time among the 12 upland cotton accessions. Taken together, these results indicated that GhGASA14 may positively regulate flowering time and respond to GA3. These findings could lead to the use of valuable genetic resources for breeding early-maturing cotton cultivars in the future.
Assuntos
Flores , Regulação da Expressão Gênica de Plantas , Giberelinas , Gossypium , Proteínas de Plantas , Gossypium/genética , Gossypium/fisiologia , Gossypium/efeitos dos fármacos , Flores/genética , Flores/efeitos dos fármacos , Flores/fisiologia , Flores/crescimento & desenvolvimento , Giberelinas/farmacologia , Giberelinas/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Filogenia , Inativação GênicaRESUMO
OBJECTIVE: This study aimed to assess the efficacy of type A botulinum toxin treatment for androgenetic alopecia (AGA) using a combination of ultrasound and trichoscopy. METHODS: Ninety patients with AGA who visited the Department of Dermatology at the Second Affiliated Hospital of Soochow University from September 2021 to December 2022 were prospectively selected. These patients met the diagnostic criteria outlined in the Chinese Guidelines for the Diagnosis and Treatment of Androgenetic Alopecia. The alopecia severity in the male patients ranged between grades 2 and 4 on the Norwood-Hamilton Scale. The patients were randomly assigned to receive injections of the same type of biological agent in a double-blind manner, with injection sites being the vertex or bilateral temporal-frontal hairline. In this study, the botulinum toxin group comprised 72 patients who received a biological agent with 100 units of type A botulinum toxin. The control group included 18 patients, and the biological agent administered to them contained 0 units of type A botulinum toxin. The patients were observed using 22-MHz ultrasound and trichoscopy before treatment, and 1 month and 3 months after treatment to compare the differences in various parameters at the injection sites. The ultrasound parameters included average follicle width, length, and count. The trichoscopy parameters were the number of hairs within a 1-cm2 area on the counting scale. No artificial interventions were performed at the injection sites, and all examination conditions were consistent. RESULTS: The patients in the botulinum toxin group had wider and longer average follicle width and length at the vertex 1 month and 3 months after treatment (p < 0.05), and wider and longer average follicle width and length in the left frontal area 3 months after treatment (p < 0.05) compared with those in the control group. The average follicle width and length gradually increased after treatment in the botulinum toxin group (p < 0.05), but no statistically significant differences were found in the control group (p > 0.05). The patients in the botulinum toxin group exhibited greater average follicle lengths after treatment at the vertex compared with the left frontal area (p < 0.05). No statistically significant differences were found in follicle count (p > 0.05) or hair count (p > 0.05) between the botulinum toxin and control groups after injection treatment. CONCLUSIONS: The follicle width and length are effective parameters for evaluating the efficacy of type A botulinum toxin treatment for AGA. Ultrasound revealed that the changes in follicles at the vertex occurred earlier than those in the left frontal area following treatment. Additionally, the changes in follicles were detected earlier than the changes in hair count using ultrasound. Ultrasound combined with trichoscopy provided more parameters for evaluating the efficacy of type A botulinum toxin treatment for AGA, resulting in a more comprehensive evaluation.
Assuntos
Alopecia , Toxinas Botulínicas Tipo A , Dermoscopia , Ultrassonografia , Humanos , Alopecia/tratamento farmacológico , Alopecia/diagnóstico por imagem , Toxinas Botulínicas Tipo A/administração & dosagem , Toxinas Botulínicas Tipo A/uso terapêutico , Masculino , Adulto , Dermoscopia/métodos , Método Duplo-Cego , Ultrassonografia/métodos , Pessoa de Meia-Idade , Resultado do Tratamento , Folículo Piloso/diagnóstico por imagem , Folículo Piloso/efeitos dos fármacos , Estudos Prospectivos , Adulto JovemRESUMO
OBJECTIVE: This study aimed to assess differences in various scalp parameters between patients with androgenetic alopecia (AGA) and healthy volunteers using 22 MHz ultrasound. METHODS: Thirty patients with AGA (AGA group) and 30 healthy volunteers (control group) who visited the Department of Dermatology at the Second Affiliated Hospital of Soochow University from September 2021 to June 2022 were randomly selected. The patients with AGA met the diagnostic criteria outlined in the Chinese Guidelines for the Diagnosis and Treatment of Androgenetic Alopecia. The severity of alopecia was assessed for males between grades 2 and 4 on the Norwood-Hamilton scale, and for females between stages 2 and 3 on the Ludwig scale. No artificial interventions were conducted at the vertex, and all examination conditions remained consistent. Ultrasound examinations at 22 MHz were performed on the scalp at the vertex in both the AGA and control groups. Seven parameters were measured, namely, epidermis + dermis thickness, entire scalp thickness, subcutaneous tissue thickness, average follicle width, average follicle length, follicle count, and the presence of color flow signals in the subcutaneous tissue. The differences in these parameters were then compared. RESULTS: The AGA group showed reduced thickness of the entire scalp and subcutaneous tissue, narrower average follicle width, shorter average follicle length, lower hair follicle count, and fewer instances of color flow signals in the subcutaneous tissue at the vertex area (p < 0.05). CONCLUSION: High-frequency (22 MHz) ultrasonography can be employed to visualize the entrance echo, dermis, subcutaneous tissue, and hair follicles of the scalp, thereby providing imaging for the clinical assessment of hair loss.
Assuntos
Alopecia , Folículo Piloso , Couro Cabeludo , Ultrassonografia , Humanos , Alopecia/diagnóstico por imagem , Alopecia/patologia , Couro Cabeludo/diagnóstico por imagem , Masculino , Feminino , Adulto , Ultrassonografia/métodos , Folículo Piloso/diagnóstico por imagem , Folículo Piloso/patologia , Pessoa de Meia-Idade , Voluntários Saudáveis , Adulto Jovem , Estudos de Casos e ControlesRESUMO
For metastatic prostate cancer, androgen deprivation therapy (ADT) is the key strategy to control the disease. However, after 18-24 months of treatment, most patients will progress from metastatic hormone-sensitive prostate cancer (mHSPC) to metastatic castration-resistant prostate cancer (mCRPC) even with ADT. Once patients enter into mCRPC, they face with significant declines in quality of life and a dramatically reduced survival period. Thus, doublet therapy, which combines ADT with new hormone therapy (NHT) or ADT with docetaxel chemotherapy, substitutes ADT alone and has become the "gold standard" for the treatment of mHSPC. In recent years, triplet therapy, which combines ADT with NHT and docetaxel chemotherapy, has also achieved impressive effects in mHSPC. This article provides a comprehensive review of the recent applications of the triplet therapy in the field of mHSPC.
RESUMO
PURPOSE: To determine the ablation efficacy of transabdominal ultrasound- and laparoscopy-guided percutaneous microwave ablation (PMWA), to investigate whether the risk of damage to adjacent organs and endometrium due to this technique can be reduced or even avoided. We also evaluated the clinical efficacy of this technique in the treatment of uterine fibroids of different sizes and at different locations over a 24-month follow-up period. METHODS: This study included 50 patients with uterine fibroids who underwent transabdominal ultrasound- and laparoscopy-guided PMWA from August 2018 to July 2020. Lesions were confirmed by pathology. The technical efficacy and complications of PMWA were assessed. The lesion diameter, lesion volume, lesion location, and contrast-enhanced ultrasound (CEUS) features before PMWA and within 24 h after PMWA were recorded. Magnetic resonance imaging (MRI) was used for follow-up at 3 and 6 months after PMWA. Transvaginal ultrasound was used for follow-up at 24 months after PMWA. RESULTS: A total of 50 patients with uterine fibroids received treatment. The median ablation rate of uterine fibroids was 97.21%. The mean lesion volume reduction rates were 32.63%, 57.26%, and 92.64% at 3, 6, and 24 months after treatment, respectively. The size and location of uterine fibroids did not significantly affect the ablation rate and the rate of lesion volume reduction. No major complication was found during and after the procedure. CONCLUSION: Transabdominal ultrasound- and laparoscopy-guided PMWA can be utilized to safely enhance the ablation rate while minimizing ablation time and avoiding harm to adjacent organs and the endometrium. This technique is applicable for treating uterine fibroids of different sizes and at varying locations. TRIAL REGISTRATION NUMBER: ChiCTR-IPR-17011910, and date of trial registration: 08/07/2017.
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Ablação por Ultrassom Focalizado de Alta Intensidade , Laparoscopia , Leiomioma , Neoplasias Uterinas , Feminino , Humanos , Micro-Ondas/uso terapêutico , Seguimentos , Leiomioma/diagnóstico por imagem , Leiomioma/cirurgia , Leiomioma/patologia , Ultrassonografia , Laparoscopia/métodos , Ablação por Ultrassom Focalizado de Alta Intensidade/métodos , Resultado do Tratamento , Neoplasias Uterinas/diagnóstico por imagem , Neoplasias Uterinas/cirurgia , Neoplasias Uterinas/patologiaRESUMO
BACKGROUND: Titanium mesh cranioplasty is the most common strategy for the repair of skull defects. However, as the frequency of cranioplasty increases, the incidence of titanium mesh exposure following cranioplasty increases as well. This study aimed to investigate the methods and outcomes of plastic surgery in the management of titanium mesh exposure following cranioplasty. METHODS: Patients with titanium mesh exposure following cranioplasty were retrospectively selected from January 2016 to August 2021. Titanium mesh exposure was corrected with reconstructive plastic surgery, including skin grafting, expander insertion, partial removal of the exposed mesh, replacement of the mesh, or flap transplantation. RESULTS: This study included 21 patients with titanium mesh exposure with surgical site infection and a variant of scalp deformity. The age of the patients ranged from 18 to 74 years, with the mean age being 54 years. All patients underwent reconstructive plastic surgery and exhibited complete wound healing. The follow-up period ranged from 17 to 90 months. One patient experienced titanium mesh re-exposure and subsequently underwent an additional procedure for the partial removal of the exposed mesh. No serious complications were observed postoperatively. CONCLUSION: Reconstructive plastic surgery can facilitate wound healing at the titanium mesh exposure site following cranioplasty. However, an individualized treatment strategy is required for each patient, and complications should be managed by adopting standard measures.
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Procedimentos de Cirurgia Plástica , Crânio , Telas Cirúrgicas , Infecção da Ferida Cirúrgica , Titânio , Humanos , Pessoa de Meia-Idade , Masculino , Adulto , Feminino , Procedimentos de Cirurgia Plástica/métodos , Estudos Retrospectivos , Idoso , Adolescente , Crânio/cirurgia , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/cirurgia , Retalhos Cirúrgicos , Adulto Jovem , Cicatrização , Complicações Pós-Operatórias/cirurgia , Transplante de PeleRESUMO
BACKGROUND: Positioning implant components and restoring patient anatomy during total hip arthroplasty (THA) are essential for joint stability, polyethylene liner wear, and range of motion. Previous studies comparing intraoperative fluoroscopy with no fluoroscopy during the posterior or posterolateral approach have reported conflicting results. This meta-analysis evaluated if intraoperative fluoroscopy improves component positioning and femoral component position compared to no fluoroscopy during posterior or posterolateral approach total hip arthroplasty. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards were followed when conducting the systematic review. We searched Web of Science, Embase, PubMed, Cochrane Controlled Trials Register, Cochrane Library, Highwire, CBM, CNKI, VIP, and Wanfang database in May 2023 to identify studies involving Intraoperative fluoroscopy versus no fluoroscopy during posterior or posterolateral approach total hip arthroplasty. Finally, we identified 1133 patients (1145 hips) assessed in seven studies. RESULTS: There were no significant differences in terms of acetabular cup inclination angle (ACIA, P = 0.43), ACIA within safe zone rate (P = 0.58), acetabular cup anteversion angle (ACAA, P = 0.46); ACAA within safe zone rate (P = 0.72), Combined safe zone rate (P = 0.28), dislocation rate (P = 0.64) and infection rate (P = 0.94) between two groups. Compared with the no fluoroscopy group, the intraoperative fluoroscopy group had more operation time (P < 0.00001), less femoral component offset difference (FCOD, P = 0.03), and less LLD (P < 0.00001). CONCLUSION: Even though intraoperative fluoroscopy was not related to an improvement in cup location or dislocation incidence. Our findings demonstrate that the restoration of leg lengths and femoral offset can be significantly improved by using intraoperative fluoroscopy to supplement good surgical skills in THA. The advantages of intraoperative fluoroscopy might become more apparent for surgeons with less experience. To ascertain whether intraoperative fluoroscopy for posterior or posterolateral approach total hip arthroplasty will have clinical benefits and improve the survival of prostheses, more well-powered and well-designed long-term follow-up studies were necessary.
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Acetábulo , Artroplastia de Quadril , Humanos , Fluoroscopia/métodos , Artroplastia de Quadril/métodos , Acetábulo/cirurgia , Acetábulo/diagnóstico por imagem , Prótese de QuadrilRESUMO
Based on the insulin receptor substrate(IRS)/phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt) pathway, the intervention effect of Yupingfeng Powder on type 2 diabetes mellitus(T2DM) rats was studied, and the potential mechanism of improving T2DM hepatic insulin resistance was explored. A T2DM rat model was established by feeding with high-fat and high-sugar feed combined with intraperitoneal injection of streptozotocin. Successfully modeled rats were selected and divided into a model group, a positive control group(MET), and a Yupingfeng Powder group. At the same time, a blank group was set up, and corresponding drugs were given by gavage. The model group and blank group were given an equal amount of physiological saline by gavage. During the experiment, body mass and fasting blood glucose were regularly measured, and glucose tolerance and insulin tolerance were measured at the end of the experiment. After the experiment, the levels of blood glucose, insulin, blood lipids, and related liver function indicators were measured; changes in liver pathological damage were observed, levels of liver monoamine oxidase were detected, and qRT-PCR was used to detect mRNA expression levels of IRS/PI3K/Akt pathway related genes. Compared with the model group, the Yupingfeng Powder group had an increase in body weight, a decrease in fasting blood glucose, fasting insulin, and steady-state model evaluation index, a decrease in the area under the curve of glucose tolerance and insulin tolerance tests, a decrease in serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol content, and an increase in high-density lipoprotein cholesterol content. Compared with the model group, the Yupingfeng Powder group showed a decrease in liver monoamine oxidase levels, a decrease in serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total bilirubin levels, and an increase in total protein and albumin levels. Hematoxylin-eosin(HE) staining showed a reduction in pathological liver cell damage. Compared with the model group, the Yupingfeng Powder group showed a significant increase in the mRNA expression levels of IRS1, PI3K, and Akt in the liver of rats, as well as a significant decrease in the mRNA expression levels of interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α). This indicates that Yupingfeng Powder can regulate the IRS/PI3K/Akt signaling pathway and glucose and lipid metabolism disorders, increase insulin sensitivity, improve hepatic insulin resistance, and thus play a therapeutic role in T2DM.
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Diabetes Mellitus Tipo 2 , Medicamentos de Ervas Chinesas , Proteínas Substratos do Receptor de Insulina , Resistência à Insulina , Fígado , Fosfatidilinositol 3-Quinases , Pós , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Ratos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/administração & dosagem , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fígado/metabolismo , Fígado/efeitos dos fármacos , Masculino , Proteínas Substratos do Receptor de Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Transdução de Sinais/efeitos dos fármacos , Ratos Sprague-Dawley , Glicemia/metabolismo , Insulina/metabolismo , HumanosRESUMO
Shenling Baizhu San(SLBZS) is a commonly used medicine for the treatment of ulcerative colitis(UC). This study aims to explore the mechanism of SLBZS in treating UC by using colonic metabolomics and network pharmacology. BALB/c mice were randomly divided into four groups: a blank group, a model group, an SLBZS group, and a sulfasalazine group. UPLC-Q-TOF-MS/MS technology was utilized to analyze the metabolic profiles of colonic tissue in mice, and differential metabolites and related metabolic pathways were screened. Based on the online database, active ingredients, action targets, and UC disease targets of SLBZS were screened. The protein-protein interaction(PPI) network of core targets of SLBZS in treating UC was constructed using STRING and Cytoscape 3.9.1. Gene Ontology(GO) functional and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses were performed using the DAVID database. A "metabolite-reaction-enzyme-gene" network was constructed to conduct a combined analysis of metabolomics and network pharmacology. SLBZS reversed the levels of 25 metabolites involved in various pathways such as D-glutamine and D-glutamate metabolism, caffeine metabolism, sphingolipid metabolism, arginine biosynthesis, lysine degradation, alanine, aspartate, and glutamate metabolism, glycerophospholipid metabolism, and pyrimidine metabolism in UC colonic tissue. 47 core targets of SLBZS in treating UC were involved in pathways including the MAPK signaling pathway, TNF signaling pathway, Toll-like receptor signaling pathway, lipid and atherosclerosis, inflammatory bowel disease, and Th17 cell differentiation. Integrated analysis showed that glycerophospholipid metabolism and pyrimidine metabolism were key metabolic pathways in the treatment of UC with SLBZS. The results suggested that SLBZS improved colonic mucosal morphology by regulating colonic metabolites, down-regulated the expression of inflammation-related core target genes to reduce inflammation levels, and alleviated lipid metabolism disorders, thereby exerting a therapeutic effect on UC.